Vantage Snippets are short summaries of breaking news stories.
A Covid-19 diagnosis first this week has come as a result of different approaches and technologies converging. Quidel has gained US FDA authorisation for the first test for both the coronavirus and flu that works by detecting viral antigens rather than RNA. Nicknamed the ABC test because it tests for influenza A and B as well as Covid-19, the Sofia 2 Flu + Sars Antigen assay detects the nucleocapsid protein from the three viruses in a single nasal swab. It may be used at the point of care, returning results inside 15 minutes, and Quidel claims impressive accuracy, as shown below. With Covid-19 cases on the rise in many countries and the flu season getting under way in the Northern hemisphere, this kind of combination test could help save money. Quidel was the first company to gain authorisation for an antigen test for Covid-19 in mid-July. Another antigen test, this time developed by New Jersey-based Access Bio, was also authorised last week. Access now has the FDA’s rubber-stamp for all three main types of Covid-19 tests, its molecular and antibody assays having been authorised in July.
|Accuracy figures for Quidel's ABC test|
|Virus||PPA vs PCR (%)||NPA vs PCR (%)|
|Sensitivity vs culture (%)||Specificity vs culture (%)|
|Note: PPA and NPA are analogous to sensitivity and specificity, respectively. Source: company release.|
Note: "other" includes six antigen tests, three home sampling kits and two IL-6 tests.
Sometimes medtech acquisitions are prompted when groups consolidate as a defence against difficult market conditions; Smith & Nephew’s purchase of Integra Lifesciences’s extremity implants last month was arguably one such. But sometimes the opposite occurs, with a buyer targeting technologies in high demand. Steris’s swoop on Key Surgical for $850m is one of the latter. Part of Chicago-based investor Water Street Healthcare Partners’ portfolio, Key Surgical is, like its new owner, focused on sterilisation. It offers devices used in operating theatres as well as protective equipment such as face shields, masks and gloves, for which there is an obvious and pressing need. Financed with debt and cash, the deal is set to close by the end of the year and be accretive to top-line growth, margins and earnings, Steris says, with Key Surgical expected to see revenue of around $170m and adjusted EBIT of $50m this year. The deal also comes with an tax benefit which ought to reduce the effective purchase price to around $810m. More pandemic-inspired deal-making might be welcomed by bankers: though the Key Surgical acquisition is worth less than $1bn it is still the fifth biggest announced so far this year.
|Top 5 medtech M&A announced in 2020|
|Aug 5||Teladoc Health||Livongo||18,500||Digital health|
|Aug 2||Siemens Healthineers||Varian Medical Systems||16,400||Diagnostic imaging|
|Sep 20||Illumina||Grail||8,000||Diagnostic imaging|
|Jun 22||Invitae||Archer DX||1,400||In vitro diagnostics|
|Oct 6||Steris||Key Surgical||850||General hospital & healthcare supply|
Gilead’s Veklury blazed a trial for Covid-19 antivirals, but there remains much room for improvement: final results from a pivotal trial have confirmed the drug’s modest benefits, with a narrow group of patients benefiting the most. A couple of oral antivirals are seeking to offer more, and Merck & Co’s Ridgeback-partnered MK-4482, or molnupiravir, is most advanced. Two phase IIb studies are poised to start, recruiting almost 2,000 subjects. Meanwhile phase II data should emerge any day; these studies initially tested 200mg and 300mg, but higher doses were added, delaying readout. According to clinicaltrials.gov 200mg, 400mg and 800mg will be taken in phase IIb. Elsewhere, the first data on Biocryst’s galidesivir are also due later this year, from a phase I trial conducted in Brazil. And, while this is not strictly an antiviral, but said to have those properties, Abivax’s ABX494 is in the 1,000-patient Mir-Age trial. Finding a survival benefit remains the ultimate goal for any Covid-19 treatment, and while antibody approaches are considered more likely to hit this mark the cost and convenience advantages of these small-molecule antivirals should not be underestimated.
|Covid-19 antivirals – ones to watch|
|MK-4482||Merck & Co (Ridgeback)||Viral RNA polymerase inhibitor||Phase IIb in hospitalised and non-hospitalised patients; endpoints include mortality and recovery measures to day 29; recruitment starts late Oct||NCT04575584; NCT04575597|
|ABX464||Abivax||RNA CBC regulator; miRNA-124 expression stimulant; Rev inhibitor||Trial selects for high risk patients; primary endpoint rate of patients not requiring mechanical ventilation and who are alive; interim analysis, after 300 subjects, due YE'20; final readout Q1'21||NCT04393038|
|Galidesivir||Biocryst||Viral RNA polymerase inhibitor||BARDA/NIAID sponsored; phase I results will determine push into phase II||NCT03891420|
|Source: EvaluatePharma, company statements, clinicaltrials.gov.|
The sellside was quick today to shrug off a delay to Iovance’s lead project, lifileucel, in metastatic melanoma. But the fact the company cannot agree with the FDA on the potency assays needed for its BLA submission highlights yet another potential stumbling block for the real-world use of tumour-infiltrating lymphocytes (TILs). As Iovance’s TILs are simply extracted from a person’s tumour and expanded before being reinfused, therapy will vary from patient to patient – and the active targets are also likely to differ, Stifel analysts noted, unlike with CAR-T, for example. This will make standardising TIL therapy tricky, and the FDA is obviously keen to cut down on variability as much as possible. Iovance seems confident that it can “refine” its potency assay data and file lifileucel in 2021; it had previously expected to submit by the end of this year. Both Stifel and Mizuho analysts remain hopeful of approval in 2022, based on the data released so far. But the potency issue comes on top of questions around whether TILs are patentable or economically viable, and Iovance stock opened down 12% this morning. Other TIL players take note.
|Selected TIL approaches in development|
|Company||Lead TIL project||Status|
|Iovance Biotherapeutics||Lifileucel||Melanoma filing delayed until 2021|
|Achilles Therapeutics||ATL001||Ph1/2 in melanoma (NCT03997474) & NSCLC (NCT04032847)|
|Tilt Biotherapeutics||TILT-123 (oncolytic adenovirus) + TILs||Ph1, NCT04217473|
|Genocea Biosciences||GEN-011||IND filed in Sept 2020|
Source: EvaluatePharma, clinicaltrials.gov.
This story has been updated to clarify that TILT-123 is an oncolytic adenovirus, and to add Genocea's GEN-011.
The days of gene therapy companies making huge gains off data in very small numbers of patients might be over. Axovant today put out ostensibly promising results with its Parkinson’s gene therapy, AXO-Lenti-PD, but these only came from two patients in a cohort of four. The markets were not impressed: Axovant’s stock initially rose in premarket trading, but was down 20% in morning trade. On the plus side, AXO-Lenti-PD cleared the bar set by Axovant, at least in the two evaluable patients from the second cohort of the Sunrise-PD phase II trial. At six months, they had a 21-point mean improvement in the UPDRS Part III “off” score; the target had been at least 10-15 points, in line with deep brain stimulation. The results look similar to those from the lower-dose cohort one of Sunrise-PD, but better than those seen with Voyager/Neurocrine’s VY-AADC in its 15-patient phase Ib study. However, the usual caveats about cross-trial comparisons are even more relevant with such small patient numbers. Axovant will need to show more to convince investors – it will test a higher volume and flow rate in cohort three of Sunrise-PD, and start the sham-controlled Explore-PD study next year.
|Cross-trial comparison of Parkinson's gene therapy candidates|
|Company||Project||Trial details||N||Improvement in UPDRS Part III “off” score|
|Axovant Gene Therapies||AXO-Lenti-PD||Sunrise-PD (NCT03720418), cohort 1 (4.2x106 TU)||2||22 points at 1yr|
|Sunrise-PD (NCT03720418), cohort 2 (1.4x107 TU)||2||21 points at 6mo|
|Voyager Therapeutics/ Neurocrine Biosciences||NBIb-1817 (VY-AADC)||PD-1101, NCT01973543||15||10-19 points at 3yrs across cohorts|
|PD-1102, NCT03065192||7||12 points at 2yrs|
|Source: Company presentations, clinicaltrials.gov.|
Biopharma press releases rarely conjure thoughts of burlesque, but yesterday Amgen left observers wanting a lot more. The group said a “potentially registrational” phase II trial of its closely-watched Kras inhibitor, sotorasib, in advanced lung cancer was positive, without disclosing any data. All Amgen revealed was that response rates were consistent with phase I data; most recently presented at Esmo, these showed a 35% ORR and a median duration of response of 10.9 months. Analysts believe that DOR needs to hit at least six months in phase II to give sotorasib a chance at early approval, and the sellside widely interpreted Amgen’s release to mean that this had been achieved, and even beaten; Leerink went so far as to predict that 10-11 months could emerge. It will be a while before the numbers from the phase II portion of the Codebreak 100 study are revealed – full data are not due until January, at the World Lung conference. Amgen did give a clear hint that it believes the data are good enough to file on, however, saying that talks with regulators will now commence. A thin late-stage pipeline explains Amgen’s need for speed here; the Kras inhibitor is the group’s third most valuable pipeline project, according to EvaluatePharma.
|A lot riding on KRAS: Amgen's pipeline prospects|
|Project||Details||20206e sales ($m)||NPV ($m)|
|ABP 798||Rituxan biosimilar||191||1,412|
|AMG 510 (sotorasib)||KRAS G12 inhibitor (lung and colorectal cancers)||951||4,826|
Anti-TSLP MAb (asthma and COPD)
|ABP 959 (eculizumab)||Soliris biosimilar||816|
|Omecamtiv mecarbil||Cardiac myosin activator (heart failure)||422||815|
|AMG 420||Anti-BCMA & CD3 bispecific (myeloma)||19||92|
|ABP 494||Erbitux biosimilar||49||363|
|Note: includes only products for which the sellside is estimating sales. Source: EvaluatePharma.|
Friday marked an unusual coup for Bristol Myers Squibb’s Opdivo plus Yervoy combo: a US green light for front-line mesothelioma made it the first approval in 16 years for this hard-to-treat cancer. The sharp-eyed will also have noticed the unexpected breadth of the approval, which came in all-comers, even though the supporting study, Checkmate-743, clearly showed the effect to be driven by the 25% of subjects who had the non-epithelioid histology and represent a minority of mesothelioma patients. There was an impressive 56% reduction in risk of death versus chemo among non-epithelioids given the combo in the study, but those with epithelioid histology had a non-significant 15% reduction. It will be up to Bristol to make the most of the advantage, especially as its checkpoint blocker competition is nowhere to be seen. Keytruda’s indication-agnostic approvals mean that some mesothelioma patients can receive the Merck & Co drug, and indeed the Keynote-158 trial, which forms part of the basis for these, did include several with this cancer. But Keytruda recently failed the late-line Promise-meso study, and all phase III trials in this indication except Checkmate-743 have academic groups as primary sponsor.
|Selected phase III studies of anti-PD-(L)1 drugs in mesothelioma|
|Study||Design||Setting||Primary endpoint(s)||Primary sponsor||Data?|
|Bristol Myers Squibb|
|Checkmate-743||Opdivo + Yervoy, vs chemo||1L||OS||Bristol Myers Squibb||mOS 18.1mth vs 14.1mth (p=0.002); mOS in epithelioid 18.7mth vs 16.2mth|
|Confirm||Opdivo vs placebo||≥2L||PFS & OS||University of Southampton||Primary completion Jul 2021|
|Merck & Co|
|IFCT-1901||Keytruda +/- chemo, vs chemo||1L||PFS & OS||Canadian Cancer Trials Group||Primary completion Jul 2022|
|Promise-meso||Keytruda vs chemo||≥2L||PFS||European Thoracic Oncology Platform||Fail: HR for PFS 1.06; mOS 10.7mth vs 11.7mth|
|Dream3R||Imfinzi +/- chemo, vs chemo||1L||OS||PrECOG, LLC||Yet to get under way|
|Beat-meso||Tecentriq + Avastin + chemo, vs Avastin + chemo||1L||PFS & OS||European Thoracic Oncology Platform||Primary completion Oct 2024|
|Source: clinicaltrials.gov & scientific papers.|
Ten more Covid-19 diagnostics received emergency use authorisation from the US FDA last week – among them a test for IL-6. Perhaps the agency believes that IL-6-targeting drugs could still have a role to play, despite several failures. Beckman Coulter’s Access IL-6 test, which got the nod on Thursday, joins Roche’s Elecsys IL-6 test, authorised in June. Both are used to identify Covid-19 patients who could be at high risk of needing mechanical ventilation – IL-6 has been found to be elevated in some patients with severe disease. Beckman says that monitoring IL-6 levels could help doctors treat patients before they need a ventilator, but it does not specify what this treatment might be. The jury is still out on anti-IL-6 MAbs: Sanofi’s Kevzara has flopped twice, while Roche’s Actemra failed in the Covacta study. However, more recently, Roche claimed a win in the Empacta trial, with hospitalised patients receiving Actemra 44% less likely to progress to mechanical ventilation or death than those receiving placebo. Still, there was no difference in mortality. The Remdacta study, of Actemra in combination with Gilead’s remdesivir, is yet to read out.
Despite a positive panel meeting Mesoblast’s paediatric graft-versus-host disease treatment Ryoncil still received a knockback from the US FDA, featuring as one of three rejections last month. Still, those concerned that the FDA is tightening up will have been relieved that Gavreto received an early green light in Ret fusion-positive NSCLC. Lilly’s Retevmo is already approved in the setting, but comes with a warning about QT prolongation, something Gavreto’s label does not include. Roche will co-commercialise Gavreto with Blueprint in the US after paying $650m up front for rights. Elsewhere, Glaxosnithkline's Nucala became the first biological approved in the US for hypereosinophilic syndrome, some way ahead of Astrazeneca’s Fasenra, which recently started a pivotal study in this setting. Glaxo is still due a decision on dostarlimab, a latecomer to the anti-PD-1 class, in recurrent endometrial cancer; a decision is expected before the year end.
|Notable first-time US approval decisions in September|
|Project||Company||Sales by indication ($m)||Outcome|
|Dostarlimab||Glaxosmithkline||523||No decision yet|
|Onureg (CC-486)||Bristol Myers Squibb||466||Approved|
|Gavreto (pralsetinib)||Roche/Blueprint||109*||Approved (~2 mths early)|
|Alaway Preservative Free ophthalmic solution (EM-100)||Eton/Bausch||-||Approved|
|*Forecast doesn’t include Roche numbers. Sources: company releases & EvaluatePharma.|
|Supplementary and other notable approval decisions in September|
|Product||Company||Indication (clinical trial)||Outcome|
|Fetroja/Cefiderocol||Shionogi||Hospital-acquired bacterial pneumonia & ventilator-associated bacterial pneumonia (APEKS-NP)||Approved|
|Trelegy Ellipta||Glaxosmithkline||Asthma (Captain)||Approved|
|Trulicity||Lilly||3mg and 4.5mg doses for type 2 diabetes (Award-11)||Approved|
|Nucala||Glaxosmithkline||Hypereosinophilic syndrome (NCT02836496)||Approved|
|Kalydeco||Vertex||Cystic fibrosis patients aged 4-6 months (Arrival)||Approved|
|Xeljanz||Pfizer||Children & adolescents with active polyarticular course juvenile idiopathic arthritis (NCT02592434)||Approved|
|Xolair||Novartis||Nasal polyps (Polyp 1 and 2)||No decision yet|
|Sources: Sources: company releases & EvaluatePharma.|
Covis Pharma is owned by private equity and, if past deals are anything to go by, run by executives more focused on cash flows than R&D. Thus the acquisition of Amag seems something of a departure, considering that the main draw is a project that still requires substantial development. Ciraparantag is a reversal agent believed to be active against heparin as well as the novel, oral anticoagulants Pradaxa, Eliquis, Xarelto and Savaysa. There is a need here: Andexxa, now owned by Alexion after its $1.4bn Portola takeover, is approved against Eliquis and Xarelto, but carries black box warnings; Boehringer Ingelheim’s Praxbind only reverses that company’s Pradaxa. As a small molecule ciraparantag could offer a more convenient, safer and faster-acting option, Amag argued – although this still needs to be proven in phase III. Step forward Covis, which this week agreed to pay almost $500m for Amag, net of debt. Perhaps the hope is that Daiichi Sankyo, which sells Savaysa, will step in as a development partner; the Japanese group previously co-sponsored an earlier trial. The sellside estimates launch in 2023 and sales of $10m by 2026, according to EvaluatePharma. Covis is surely hoping for much more.